PROJECT SUMMARY/ABSTRACT The overall goal of this application is to investigate molecular and cellular mechanisms of tau-induced autophagic dysfunctions in Alzheimer's disease (AD) and related dementias. While impairments of autophagy - the major cellular clearance system - are significant and widespread in AD, the underlying mechanisms remain enigmatic. On the one hand, aberrant tau species and the aggregates that form are extremely heterogeneous both in terms of structure and function and likely impact autophagy at different steps and through distinct mechanisms. On the other hand, the autophagy system is highly complex and further connects within a vesicular continuum to endosomal, lysosomal, and secretory pathways. Dysfunctions at any given stage results in re-routing of cargo within the system, making it extremely challenging to distinguish neurotoxic causes from adaptive consequences. In order to truly understand the dynamics of the system, multiple aspects of the different pathways must be studied in parallel to pinpoint the initial insult. We hypothesize that imbalance of specific, selective autophagy pathways contributes to the pathogenesis of AD and related dementias. This proposal will investigate how tau impacts the autophagy system and how dysfunctions in selective autophagy pathways contribute to tau processing, aggregation, and toxicity in 3 coordinated aims. In aim 1 we will perform comprehensive analyses of the autophagy landscape in the context of tau pathology in human post-mortem brain to reveal their relationship in AD and to approximate stages/routes at which autophagy is blocked. In aim 2 we will validate the impact of individual tau species and measure the dynamic autophagy response in screenable neuronal systems and patient-derived cells over time. In aim 3 we will translate our findings into pre-clinical animal models to validate the interactions between specific tau species and selective autophagy pathways in a comprehensive in vivo approach. The proposed rigorous analysis of various biological and pathological aspects will dissect causes from consequences and reveal the cross-talk between tau and selective autophagy signaling pathways towards development of biomarkers and therapeutic interventions in the future.